The Global Alagille Alliance study: Redefining the natural history of Alagille syndrome
Authors: Nawras Habash, Samar H. Ibrahim
Journal: Hepatology (2022)

Alagille syndrome (ALGS) is an autosomal dominant inherited disorder with multisystemic manifestations. It has an estimated frequency of one in 30,000. Mutations involving one of two genes: Jagged 1 (JAG1) and neurogenic locus notch homolog protein 2 (NOTCH2) are responsible for ALGS. Ninety‐four percent of patients who meet the diagnostic criteria for ALGS have mutations in JAG1, whereas mutations in NOTCH2 account for 2%–3% of ALGS cases.1,2 ALGS is an autosomal dominant disorder that does not breed true within families with no defined genotype–phenotype correlation, suggesting that genetic modifiers or environmental factors can affect disease phenotype.1,2 From the hepatic standpoint, ALGS is characterized by hepatic duct paucity and variable degrees of cholestasis.1,2 Extrahepatic manifestations of ALGS are variable and include characteristic facies, cardiac, renal, skeletal, and ocular abnormalities. Data describing the natural history of ALGS were limited to studies from North American or European tertiary centers. Such studies potentially overestimated the severity of hepatic involvement in ALGS because of referral bias.3 Historically, the lack of large international studies, compounded by the significant variability in the presentation among patients with ALGS, and the absence of genotype–phenotype correlation hampered the characterization of the natural history of ALGS and the discovery of prognostic markers to predict disease severity and outcome. The success of defining the natural history of rare diseases rests on the strength of well‐curated large databases such as the Global Alagille Alliance (GALA). The GALA encompasses the largest global cohort of patients with ALGS that was established in 2018 and included 67 centers from 29 different countries.4 In the current study by Vandriel et al.,4 1433 pediatric patients from the GALA study with clinical or genetically confirmed ALGS diagnoses born between 1997 and 2019 were enrolled, representing the largest and the most geographically inclusive cohort of pediatric patients with ALGS to date. The study aims to explore the "real‐world" natural history of ALGS, including survival with native liver, potential serum biomarkers that could predict long‐term hepatic outcomes, and, lastly, describing the global patient and graft survival following liver transplant in pediatric patients with ALGS. The authors report a previously unrecognized significant liver disease burden with 95% of all the patients having liver involvement at any given time, 85% having neonatal cholestasis, and 24% having xanthomas. Previous studies indicated that between 20% and 75% of patients with ALGS require liver transplantation.3,5 In contrast, in this study, 40% of the patients reached adulthood with their native liver, which is higher than the previously reported native liver survival rate.3 The median age of liver transplantation was 2.8 years, and 72% of liver transplantation occurred in patients younger than 5 years of age. Cholestasis and its sequelae (pruritus, xanthomas, and fat‐soluble vitamin deficiency) were the leading indication of liver transplantation followed by clinically evident portal hypertension. Graft survival rate was 83% at 18 years, and patient survival rate was 88% at 20 years following liver transplant. This rate of long‐term graft survival was achieved through careful selection of liver graft recipients and a multidisciplinary approach. Despite that, the long‐term posttransplant survival rates continue to be lower than other common indications of liver transplantation in the pediatric population (e.g., biliary atresia).6 An interesting finding of this study is the prognostic value of median total bilirubin (TB) between 6 and 12 months of life. The authors reported that 79% of patients with median TB of <5.0 mg/dl between 6 and 12 months of life reached adulthood with their native livers, whereas only 31.6% and 18.2% of patients with median TB levels between ≥5.0 and <10.0 mg/dl and ≥ 10.0 mg/dl survived into adulthood with their native livers. Along the same lines, higher median TB between the ages of 6 and12 months was associated with the risk of needing a liver transplant. Patients with median TB > 10 mg/dl had 15‐fold increased risk of liver transplantation compared with those with a median TB < 5 mg/dl. Furthermore, the prognostic value of median TB was not limited to predicting native liver survival; it also predicted the risk of developing clinically evident portal hypertension with an 8‐fold increase in patients with TB ≥ 10.0 mg/dl. The findings of the current study have significant clinical implications on the management of patients with ALGS and high median TB in the first year of life, for which close follow‐up and early referral to transplant centers is advised. Similarly, the relationship between median TB and the development of clinically significant portal hypertension can provide additional guidance on appropriate timing for esophageal varices screening. Despite the suggested predictive value of TB, counterintuitively, serum bile acids did not have any predictive value on survival of the native liver or the development of portal hypertension. This finding is secondary to the analysis being underpowered for serum bile acids when compared with median TB, as only 247 patients had serum bile acids available in the first year of life. This also highlights variations in clinical practices and access to specialized tests across the globe. On the other hand, elevated aspartate aminotransferase levels in the first year (>152 U/L) of life were associated with decreased native liver survival. Outside of informing clinical practices, the study identifies areas of future research efforts. Considering that cholestasis was the primary indication of liver transplantation in patients with ALGS—which, in part, may explain the prognostic value of TB in predicting native liver survival—therapies that target cholestasis are particularly an alluring avenue for future research. For example, the approval of the novel ileal bile acid transporter (IBAT) inhibitorsto treat patients with ALGS may represent a turning point for patients with ALGS, to the best of our knowledge, and the GALA data will be instrumental to examine how the IBAT inhibitors will alter the natural history of the disease7 by not only symptomatically treating pruritus, but also preventing liver disease progression. The success of IBAT inhibitors in the management of ALGS emphasizes the importance of, to the best of our knowledge, novel approaches for the management of cholestatic liver disease of monogenetic origin. Two classes of medications have shown promise in ameliorating cholestasis in patients with primary biliary cirrhosis and primary sclerosing cholangitis over the past few years. The first class of medications include the farnesoid X receptor activator obeticholic acid and similar agents that act through reducing the synthesis of endogenous bile acids and their toxic metabolites via a negative feedback mechanism.1 Another agent of interest is norursodeoxycholic acid (NorUDCA). NorUDCA is a side‐chain–shortened version of ursodeoxycholic acid with relative resistance to amidation that is currently studied in primary sclerosing cholangitis. NorUDCA acts through induction of cholangiocyte endogenous bicarbonate secretion.8 The role of these agents has not been examined yet in the context of cholestatic liver disease of monogenic origin, and future studies are needed. Surgical diversion of the enterohepatic circulation has also been used with limited success for the management of cholestasis and its associated pruritus in patients with ALGS, and it is a viable alternative in a subset of patients who develop drug‐associated adverse events to the IBAT inhibitors or do not have access to the IBAT inhibitors.1,9 Interestingly, the study highlights the fallibility of relying solely on histological assessment for the diagnosis of ALGS, particularly in the first 3 months of life. Notably, out of all patients who underwent liver biopsy at <3 months of age, only 65% exhibited the "classical finding" of bile duct paucity, whereas 22% had findings that are more in line with other cholestatic disorders (e.g., bile duct proliferation and ductular bile plugs seen more commonly in biliary atresia). Intriguingly, genetic testing for JAG1 and NOTCH2 was positive for pathogenic variants in 70% of patients who lacked classical findings on liver biopsy. This observation stresses the role of rapid genetic testing in patients with neonatal cholestasis when the diagnosis is uncertain to avoid unnecessary portoenterostomy that was associated with poor outcome in the study. The limitations of this study include its retrospective nature, which diminishes the ability to quantify the severity of clinically relevant hallmark symptoms with known significant ramifications on the course of ALGS (e.g., pruritus and xanthomas). Also, variations in clinical practices among different centers underpowered the analysis of key variables in the study (e.g., prognostic value of serum bile acids). Similarly, the variability in histologic scoring systems of fibrosis led to the reporting of hepatic fibrosis as a binary variable, which limited its value. In summary, the study by Vandriel et al.,4 to the best of our knowledge, provides the first real‐world, global, natural history study of pediatric patients with ALGS. This study highlighted the importance of global collaboration when studying rare diseases. The manuscript reveals a previously unrecognized high liver disease burden in patients with ALGS and emphasizes the importance of a molecular/genetic diagnosis. Unlike in patients with progressive familial intrahepatic cholestasis 2,1 the management of ALGS is not dictated by the severity of the genetic mutation and the residual protein function. Hence, the identification of an accessible and cost‐effective serum biomarker such as the serum bilirubin that can predict disease course is instrumental in risk stratifying patients with ALGS and guiding efficient health resources allocation and timely referral for liver transplantation (Figure 1).FIGURE 1: Suggested approach for the diagnosis and management of ALGS. *In institutions with access to rapid genetic test results genetic testing is often done early in the workup and in lieu of a liver biopsy. TB: total bilirubin, NLS: native liver survival, CEPH: clinically evident portal hypertension, MCT: medium chain triglyceride, UDCA: ursodeoxycholic acid, PHTN: portal hypertension, EGD: Esophagogastroduodenoscopy, HCC: hepatocellular carcinoma. [Correction added after first online publication September, 21, 2022: The abbreviated terms were updated in Figure 1; expansion on Figure 1 caption.]